Abstract

Background

Diabetes is one of the risk factors for cognitive deficits such as Alzheimer’s disease.
To obtain a better understanding of the anti-dementia effect of chotosan (CTS), a
Kampo formula, we investigated its effects on cognitive and emotional deficits of
type 2 diabetic db/db mice and putative mechanism(s) underlying the effects.

Methods

Seven-week-old db/db mice received daily administration of CTS (375 – 750 mg/kg, p.o.) and the reference
drug tacrine (THA: 2.5 mg/kg, i.p.) during an experimental period of 7 weeks. From
the age of 9-week-old, the animals underwent the novel object recognition test, the
modified Y-maze test, and the water maze test to elucidate cognitive performance and
the elevated plus maze test to elucidate anxiety-related behavior. After completing
behavioral studies, Western blotting and immunohistochemical studies were conducted.

Results

Compared with age-matched non-diabetic control strain (m/m) mice, db/db mice exhibited impaired cognitive performance and an increased level of anxiety.
CTS ameliorated cognitive and emotional deficits of db/db mice, whereas THA improved only cognitive performance. The phosphorylated levels
of Akt and PKCα in the hippocampus were significantly lower and higher, respectively,
in db/db mice than in m/m mice. Expression levels of the hippocampal cholinergic marker proteins and the number
of the septal cholinergic neurons were also reduced in db/db mice compared with those in m/m mice. Moreover, the db/db mice had significantly reduced levels of vasculogenesis/angiogenesis factors, vascular
endothelial growth factor (VEGF), VEGF receptor type 2, platelet-derived growth factor-B,
and PDGF receptor β, in the hippocampus. CTS and THA treatment reversed these neurochemical
and histological alterations caused by diabetes.